This project is focused on improving the treatment of pediatric sarcoma, a malignant neoplasm that arises in soft tissue and bone, comprising approximately 15% of all childhood cancers. These tumors are usually treated with multi-agent chemotherapy prior to surgical resection, and doxorubicin (DOX) is among the most commonly used agents. The cumulative dose limiting toxicity of DOX is irreversible damage to the heart muscle, which is a particular concern in children. Recently, thermosensitive liposomes (TSLs) containing DOX have been developed for directing the drug to a particular site in the body. When the liposomes pass through a heated region of tissue they release DOX very rapidly resulting in a local delivery of the drug. In parallel, a technology has been developed to precisel heat a region of tissue within the body using magnetic resonance imaging-guided high-intensity focused ultrasound therapy (referred to as MR-HIFU). MR-HIFU is well-suited for children because it is non-invasive and does not utilize ionizing radiation. Our hypothesis is that mild heating produced with MR-HIFU can be delivered safely in bone and soft tissue, and when combined with thermosensitive liposomes containing DOX will improve the therapeutic index of DOX. The project is divided into four aims that will evaluate important clinical issues including toxicity, safety, and local tumor control. In Aim 1, image-guided drug delivery will be performed using a clinical MR-HIFU system, and the influence of heating duration on the therapeutic index of DOX will be evaluated. In Aim 2 the reduction in DOX concentration achieved within the heart and other vital organs using this image-guided drug delivery method will be quantified. In Aim 3 a tumor growth delay experiment will be performed in a rodent model of a human pediatric sarcoma to evaluate the local control using MR-HIFU and TSLs. Finally, in Aim 4, the capability to safely heat bone and soft tissue targets using a clinical MR-HIFU system will be evaluated. A comprehensive multi-disciplinary team has been assembled to execute this research project comprised of experts in MR-HIFU, pediatric oncologists and radiologists, pharmaceutical scientists, imaging physicists, veterinary pathologists, and biostatisticians. Further, a research partnership has been formed with Philips Healthcare, a manufacturer of MR-HIFU systems, and Celsion Corporation, the manufacturer of Thermodox(r). The research team will have access to the software, hardware, and drugs necessary for delivering hyperthermia and TSLs. This innovative technology should enable the safe delivery of high-dose chemotherapy to pediatric sarcomas prior to surgical or radiation therapy, representing a significant advance in the management of this disease. If successful, this project will lead to the development of a first in kids clinical trial of MR-HIFU targeted doxorubicin delivery for pediatric sarcomas.